Self-oxygenating hydrogel: Regulation of postsurgical tumor recurrence/metastasis and wound healing

Abstract

In a recent study published in Nature Communications, Zhou et al. reported a sprayable, self-oxygenating hydrogel (HIL@Z/P/H), encapsulating photosynthetic cyanobacteria (PCC 7942), and tumor-targeted nanomedicine (HIL@Z), which could rapidly crosslink at the melanoma resection site, not only effectively inhibited tumor recurrence or metastasis but also aided in wound healing postsurgery.¹

Melanoma, a highly aggressive and metastatic cancer, predominantly relies on surgical intervention as its primary treatment modality. Despite surgical resection, the challenge persists in completely eradicating all malignant tissue, especially residual cells along the operative margins, which are particularly prone to triggering local recurrence.² As has been demonstrated, the hypoxic conditions at the surgical site promote the dissemination and distant metastasis of residual melanoma cells while perpetuating a chronic inflammatory state within the wound. This not only hampers the healing process but also constitutes a profound risk to the patient's survival and diminishes the quality of their postsurgical life.³ To minimize risks and accelerate wound recovery following surgery, radiotherapy, chemotherapy, and immunotherapy therapy are frequently employed as adjunctive treatments.^{4, 5} However, the therapeutic outcomes of these strategies often fall short of expectations and are accompanied by notable toxic side effects. Hence, the pursuit of efficacious strategies to alleviate the hypoxic microenvironment has emerged as a crucial goal.

Therefore, addressing the fundamental issue of the deteriorative hypoxic microenvironment after surgery that leads to tumor recurrence/metastasis and delayed wound healing, Zhou's group employed nanotechnology to design a therapeutic hydrogel (Figure 1A). Specifically, they noticed PCC 7942, microorganisms that harness a primitive photosynthetic system to produce oxygen in a lasting and controllable manner, making them a promising candidate to explore as an oxygen generator for alleviating hypoxia. Besides, they fabricated HIL@Z, which was composed of hyaluronic acid (HA), indocyanine green (ICG), L-arginine (L-Arg), and zeolite imidazole framework (ZIF-8). Next, they proceeded to encapsulate the PCC 7942 along with HIL@Z in situ at the surgical wound site by spraying a calcium alginate hydrogel. Noteworthy, the porous channels of the hydrogel facilitated nutrient and gas transport (Figure 1B), which can provide an ideal environment for PCC 7942 to support their long-term survival and thereby maintain consistent photosynthetic oxygenation. The photosynthetic oxygenation capability of HIL@Z/P/H did not show significant changes during 15 days of storage, demonstrating excellent stability in oxygenation efficiency (Figure 1C). After obtaining HIL@Z/P/H, Zhou and colleagues proceeded to further validate its functionality by co-culturing HIL@Z/P/H with melanoma cells. The results indicated that oxygen produced by photosynthesis of the PCC 7942 diffused into the tumor cells under the irradiation of red light at 635 nm, which ameliorated the hypoxic of microenvironment, enhanced the anticancer effect, and demonstrated the successful escape of HIL@Z/P/H from lysosome. Subsequently, they established an incomplete tumor resection model for examining the inhibitory effect of HIL@Z/P/H on recurrent metastasis of residual tumors. The results demonstrated that HIL@Z/P/H, when used in conjunction with Red laser (635 nm) and near-infrared (NIR) laser (808 nm), termed HIL@Z/P/H+Red+NIR, not only significantly inhibited tumor growth, but also led to the complete regression of some tumors in the group, with no subsequent recurrence observed. The action mechanism was that photosynthetic oxygenation could intensify PDT-induced nitrosative stress, thereby effectively promoting the death of residual tumor cells and hindering their local recurrence. Additionally, the authors employed C57BL/6 mice to establish skin defect models for evaluating the efficacy of HIL@Z/P/H in facilitating postsurgical wound healing. They found that HIL@Z/P/H facilitated the healing of surgical wounds, not only by producing oxygen through photosynthesis but also by PCC 7942 secreting extracellular vesicles. The synergy between oxygenation and the release of these extracellular vesicles lead to an increase in the level of vascular endothelial growth factor (VEGF). This heightened VEGF level, in turn, stimulated the formation of new blood vessels at the wound site, thereby accelerating the recovery process after surgery. The results of the aforementioned in vivo experiments indicated that HIL@Z/P/H contributed to the recovery following melanoma surgery and helped prevent metastasis and recurrence.

One particularly important advance made by Zhou et al. is that they found that PCC 7942 was able to downregulate the level of hypoxia-inducible factor-1α (HIF-1α). HIF-1α specifically targets and suppresses the expression of genes integral to melanoma metastasis. Meanwhile, HA on the surface of HIL@Z facilitates the active targeting to tumor cells. ZIF-8 exhibits the property of acid-responsive degradation. Thus, HIL@Z/P/H can selectively recognize tumor cells and degrade in their acidic microenvironment, thereby releasing the encapsulated photosensitizer ICG and nitric oxide (NO) donor L-Arg. Following the irradiation of ICG and L-Arg with an 808 nm NIR laser, a cascade reaction was initiated, yielding reactive oxygen species (ROS), NO, and reactive nitrogen species. This process disrupted redox homeostasis in tumor cells through enhanced glutathione metabolism, thereby efficiently inducing tumor cell death and suppressing recurrence/metastasis.

In summary, Zhou and colleagues have successfully designed and fabricated a bioactive nanocomposite hydrogel with intrinsic self-oxygenation capabilities. By harnessing the cyanobacteria's photosynthetic oxygenation, this innovative hydrogel delivered a sustained and regulatable supply of oxygen to alleviate tumor hypoxia, thereby tackling postsurgical melanoma challenges by suppressing metastatic relapse and expediting wound recovery. This study pioneers a conceptual framework in the field of biomaterials, integrating dual capacities for tumor therapeutics and tissue regeneration. Furthermore, it revealed that alleviating hypoxia significantly enhances the infiltration of macrophages and cytotoxic T cells, which holds great potential for application in combined tumor immunotherapy. Self-oxygenating hydrogel herein exemplifies a multitasking strategy. The incorporation of PCC 7942 serves as a means to supply ROS crucial for therapies highly reliant upon oxygen, such as radiation therapy and photodynamic therapy. In addition, PCC 7942 exhibits spontaneous red fluorescence, which can be harnessed for in vivo fluorescent imaging applications. We believe that advancing explorations into the utilization of cyanobacteria within the biomedical field hold significant promise, poised to yield intriguing and invaluable insights.

Xinyi Yan: Conception; drafting of the manuscript. Qi Chen: Supervision. Both authors have read and approved the final manuscript.

The authors declare no conflict of interest.

Not applicable.